Impeded Nedd4-1-Mediated Ras Degradation Underlies Ras-Driven Tumorigenesis

• DOI: 10.1016/j.celrep.2014.03.045
• Publication Date: 2014-04-17T11:49:34Z
• Authors: Taoling Zeng; Qun Wang; Jieying Fu; Qi Lin; Jing Bi; Weichao Ding; Yikai Qiao; Sheng Zhang; Wenxiu Zhao; Huayue Lin; Meilin Wang; Binfeng Lu; Xianming Deng; Dawang Zhou; Zhenyu Yin; Hong-Rui Wang
• Keywords: 0301 basic medicine; PTEN; QH301-705.5; Carcinogenesis; Nedd4 Ubiquitin Protein Ligases; Ubiquitin-Protein Ligases; Transplantation, Heterologous; 610; Mice, Nude; ONCOGENES; THERAPY; UBIQUITIN LIGASE; ACTIVATION; Mice; 03 medical and health sciences; Cell Line, Tumor; Neoplasms; Animals; Humans; TUMOR-SUPPRESSOR; EPITHELIAL NA+ CHANNEL; Biology (General); IN-VIVO; STABILITY; Endosomal Sorting Complexes Required for Transport; Epidermal Growth Factor; PTEN Phosphohydrolase; Ubiquitination; Hep G2 Cells; CANCER; 3. Good health; HEK293 Cells; NIH 3T3 Cells; HeLa Cells; Protein Binding; Signal Transduction

RAS genes are among the most frequently mutated proto-oncogenes in cancer. However, how Ras stability is regulated remains largely unknown. Here, we report a regulatory loop involving the E3 ligase Nedd4-1, Ras, and PTEN. We found that Ras signaling stimulates the expression of Nedd4-1, which in turn acts as an E3 ubiquitin ligase that regulates Ras levels. Importantly, Ras activation, either by oncogenic mutations or by epidermal growth factor (EGF) signaling, prevents Nedd4-1-mediated Ras ubiquitination. This leads to Ras-induced Nedd4-1 overexpression, and subsequent degradation of the tumor suppressor PTEN in both human cancer samples and cancer cells. Our study thus unravels the molecular mechanisms underlying the interplay of Ras, Nedd4-1, and PTEN and suggests a basis for the high prevalence of Ras-activating mutations and EGF hypersignaling in cancer.